The authors have declared that no competing interests exist.
Comparing mortality rates between patients starting HIV treatment and the general population in four African countries, Matthias Egger and colleagues find the gap decreases over time, especially with early treatment.
Mortality in HIV-infected patients who have access to highly active antiretroviral therapy (ART) has declined in sub-Saharan Africa, but it is unclear how mortality compares to the non-HIV–infected population. We compared mortality rates observed in HIV-1–infected patients starting ART with non-HIV–related background mortality in four countries in sub-Saharan Africa.
Patients enrolled in antiretroviral treatment programmes in Côte d'Ivoire, Malawi, South Africa, and Zimbabwe were included. We calculated excess mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (CIs). Expected numbers of deaths were obtained using estimates of age-, sex-, and country-specific, HIV-unrelated, mortality rates from the Global Burden of Disease project. Among 13,249 eligible patients 1,177 deaths were recorded during 14,695 person-years of follow-up. The median age was 34 y, 8,831 (67%) patients were female, and 10,811 of 12,720 patients (85%) with information on clinical stage had advanced disease when starting ART. The excess mortality rate was 17.5 (95% CI 14.5–21.1) per 100 person-years SMR in patients who started ART with a CD4 cell count of less than 25 cells/µl and World Health Organization (WHO) stage III/IV, compared to 1.00 (0.55–1.81) per 100 person-years in patients who started with 200 cells/µl or above with WHO stage I/II. The corresponding SMRs were 47.1 (39.1–56.6) and 3.44 (1.91–6.17). Among patients who started ART with 200 cells/µl or above in WHO stage I/II and survived the first year of ART, the excess mortality rate was 0.27 (0.08–0.94) per 100 person-years and the SMR was 1.14 (0.47–2.77).
Mortality of HIV-infected patients treated with combination ART in sub-Saharan Africa continues to be higher than in the general population, but for some patients excess mortality is moderate and reaches that of the general population in the second year of ART. Much of the excess mortality might be prevented by timely initiation of ART.
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981 and more than 30 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-positive people died within ten years of infection. Then, in 1996, highly active antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—was developed and the life expectancy of HIV-infected people living in affluent countries improved dramatically. Now, in industrialized countries, all-cause mortality (death from any cause) among HIV-infected patients treated successfully with ART is similar to that of the general population and the mortality rate (the number of deaths in a population per year) among patients with HIV/AIDS is comparable to that among patients with diabetes and other chronic conditions.
Unfortunately, combination ART is costly, so although HIV/AIDS quickly became a chronic disease in industrialized countries, AIDS deaths continued unabated among the millions of HIV-infected people living in low- and middle-income countries. Then, in 2003, governments, international agencies and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2007, nearly three million people living with HIV/AIDS in these countries were receiving ART—nearly a third of the people who urgently need ART. In sub-Saharan Africa more than 2 million people now receive ART and mortality in HIV-infected patients who have access to ART is declining. However, no-one knows how mortality among HIV-infected people starting ART compares with non-HIV related mortality in sub-Saharan Africa. This information is needed to ensure that appropriate health services (including access to ART) are provided in this region. In this study, the researchers compare mortality rates among HIV-infected patients starting ART with non-HIV related mortality in the general population of four sub-Saharan countries.
The researchers obtained estimates of the number of HIV-unrelated deaths and information about patients during their first two years on ART at five antiretroviral treatment programs in the Côte d'Ivoire, Malawi, South Africa, and Zimbabwe from the World Health Organization Global Burden of Disease (GBD) project and the International epidemiological Databases to Evaluate AIDS (IeDEA) initiative, respectively. They then calculated the excess mortality rates among the HIV-infected patients (the death rates in HIV-infected patients minus the national HIV-unrelated death rates) and the standardized mortality rate (SMR; the number of deaths among HIV-infected patients divided by the number of HIV-unrelated deaths in the general population). The excess mortality rate among HIV-infected people who started ART when they had a low CD4 cell count and clinically advanced disease was 17.5 per 100 person-years of follow-up. For HIV-infected people who started ART with a high CD4 cell count and early disease, the excess mortality rate was 1.0 per 100 person-years. The SMRs over two years of ART for these two groups of HIV-infected patients were 47.1 and 3.4, respectively. Finally, patients who started ART with a high CD4 cell count and early disease who survived the first year of ART had an excess mortality of only 0.27 per 100 person-years and an SMR over two years follow-up of only 1.14.
These findings indicate that mortality among HIV-infected people during the first two years of ART is higher than in the general population in these four sub-Saharan countries. However, for patients who start ART when they have a high CD4 count and clinically early disease, the excess mortality is moderate and similar to that associated with diabetes. Because the researchers compared the death rates among HIV-infected patients with estimates of national death rates rather than with estimates of death rates for the areas where the ART programs were located, these findings may not be completely accurate. Nevertheless, these findings support further expansion of strategies that increase access to ART in sub-Saharan Africa and suggest the excess mortality among HIV-infected patients in this region might be largely prevented by starting ART before an individual's HIV infection has progressed to advanced stages.
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The widespread use since 1996 of highly active antiretroviral therapy (ART) has substantially improved the prognosis of HIV-infected patients both in industrialised and low-income settings
As a result of scaling up of ART in low- and middle-income countries, 2.99 million people living with HIV/AIDS were estimated to be receiving treatment at the end of 2007, representing 31% of the estimated 9.6 million people in urgent need of treatment in these countries
We analysed data from a network of treatment programmes in sub-Saharan Africa to compare mortality rates observed in HIV-1–infected patients starting ART with non-HIV–related mortality in four countries in sub-Saharan Africa.
Analyses were based on cohorts participating in the West African and Southern African regions of the International epidemiological Databases to Evaluate AIDS (IeDEA)
Country-specific rates of all-cause mortality and HIV-free mortality by sex and 5-y age groups were obtained from the World Health Organization (WHO) Global Burden of Disease project
Information on the CD4 count, clinical stage at the start of ART, and vital status at the last contact date was missing in some patients. Vital status was considered missing if the patient was not known to have died and the last date of information was less than 2 y after starting ART or before the administrative closure date of the cohort, whatever came first. We used multiple imputation by chained equation methods to impute missing information
We quantified mortality of HIV-infected patients on ART relative to the mortality in the general population using excess mortality and standardised mortality ratios (SMRs). The excess mortality risk is derived using an additive model, by subtracting age- and sex-specific HIV-unrelated mortality rates in the reference population from mortality in HIV-infected patients. SMRs are based on a multiplicative model and calculated as the ratio of the number of observed deaths over the expected deaths, using age- and sex-specific rates of HIV-unrelated mortality from the reference population. The SMR thus quantifies how much higher mortality is in HIV-infected patients compared to the reference population, but gives no indication of the excess mortality in absolute terms. Excess mortality and SMRs with 95% confidence intervals (CIs) were obtained from generalised linear models with a Poisson error structure, as described by Dickman and colleagues
Multivariable models were calculated for excess mortality on the 20 imputed datasets. The interpretation of the excess hazard ratios (eHRs) from these models is similar to that of the hazard ratio in the familiar Cox model. For example, an eHR of 0.80 for females relative to males would indicate that females have a 20% lower risk of death as compared to males, after controlling for the variation in background mortality. The following variables were included: age, sex, ART regimen, baseline CD4 cell count, clinical stage of disease, and calendar period of starting ART. Time periods considered were months 1–3, 4–6, 7–12, and 13–24 after start of ART. ART regimen was defined as non-nucleoside reverse transcriptase inhibitor (NNRTI)-based, protease inhibitor (PI)-based, and other. Baseline CD4 count was analysed in five categories (0–24, 25–49, 50–99, 100–199, and 200 or more cells/µl). Clinical stage of disease was defined as less advanced (WHO stage I or stage II) or advanced (WHO stage III or stage IV). In a sensitivity analysis we excluded two sites with high loss to follow-up. All analyses were done in Stata version 10.0 (Stata Corporation), using the “ice” routine for imputation of missing values.
The combined dataset included 13,249 patients.
Programme | Country | Number of Patients | Median Age (IQR) | Number of Women (%) | Median (IQR) Baseline CD4 (Cells/µl) | Number in WHO stage III/IV at Baseline (% |
Number of Patients Lost to Follow-up at 2 y | Cumulative Loss to Follow-up (95% CI) at 2 y (%) |
Cumulative Mortality (95% CI) at 2-y (%) | |
Crude | Following Multiple Imputation |
|||||||||
Côte d'Ivoire | 2,400 | 35 (30–42) | 1,770 (74) | 131 (51–217) | 1,939 (82) | 218 | 13.7 (12.1–15.6) | 10.6 (9.3–12.1) | 11.2 (9.7–12.8) | |
Zimbabwe | 857 | 37 (32–44) | 585 (68) | 102 (51–159) | 263 (68) | 33 | 7.1 (5.1–9.8) | 7.4 (5.7–9.6) | 7.5 (5.6–9.6) | |
South Africa | 1,916 | 33 (29–39) | 1,310 (68) | 103 (50–160) | 1,528 (80) | 62 | 7.6 (5.9–9.7) | 11.1 (9.5–13.1) | 11.1 (9.2–12.8) | |
South Africa | 3,366 | 32 (28–38) | 2,353 (70) | 87 (35–146) | 3,018 (90) | 148 | 7.1 (6.1–8.4) | 11.2 (10.1–12.4) | 11.3 (10.2–12.5) | |
Malawi | 4,710 | 36 (30–42) | 2,813 (60) | 126 (54–211) | 4,063 (86) | 829 | 31.7 (29.9–33.6) | 12.3 (11.1–13.6) | 13.2 (11.9–14.4) | |
— | 13,249 | 34 (29–41) | 8,831 (67) | 107 (46–175) | 10,811 (85) | 1,290 | 16.2 (15.4–17.1) | 11.1 (10.5–11.8) | 11.7 (11.1–12.3) |
Number of patients (%) unless otherwise indicated.
Percent of patients with known clinical stage at baseline.
Estimated for patients with at least one additional potential year of follow-up until administrative censoring date of the database of their programme.
Outcomes imputed in patients lost to follow-up.
CEPREF, Centre de Prise en Charge de Recherches et de Formation/Agence National de Recherches sur le Sida (ANRS) 1203 cohort.
Information on the CD4 count and clinical stage at the start of ART was missing for 2,535 patients (19.1%) and 529 patients (4.0%), respectively. Total follow-up time after imputation increased to 17,480 y, and the number of deaths to 1,338. Mortality estimates at 2 y were somewhat higher after imputation for the Centre de Prise en Charge de Recherches et de Formation (CEPREF) and Lighthouse cohorts, but similar to the crude estimates in the other cohorts (
Category | Subcategory | Original Data | Following Multiple Imputation |
||||
Person-Years | Person-Years | ||||||
13,249 (100) | 14,695 | 1,177 (100) | 13,249 (100) | 17,480 | 1,338 (100) | ||
3,436 (26) | 3,856 | 276 (23) | 3,436 (26) | 4,564 | 309 (23) | ||
— | 5,875 (44) | 6,567 | 521 (44) | 5,875 (44) | 7,789 | 594 (44) | |
— | 2,919 (22) | 3,232 | 266 (23) | 2,919 (22) | 3,851 | 308 (23) | |
— | 1,019 (8) | 1,041 | 114 (10) | 1,019 (8) | 1,276 | 127 (10) | |
8,831 (67) | 10,047 | 701 (60) | 8,831 (67) | 11,796 | 789 (59) | ||
— | 4,418 (33) | 4,648 | 476 (40) | 4,418 (33) | 5,684 | 549 (41) | |
11,325 (85) | 12,616 | 1,027 (87) | 11,325 (85) | 14,969 | 1162 (87) | ||
— | 94 (1) | 124 | 8 (1) | 94 (1) | 148 | 9 (1) | |
— | 1,830 (14) | 1,955 | 142 (12) | 1,830 (14) | 2,363 | 167 (12) | |
1,670 (13) | 1,753 | 322 (27) | 1,937 (15) | 2,414 | 415 (31) | ||
— | 1,188 (9) | 1,303 | 162 (14) | 1,457 (11) | 1,884 | 225 (17) | |
— | 2,174 (16) | 2,571 | 182 (15) | 2,725 (21) | 3,737 | 275 (20) | |
— | 3,812 (29) | 4,408 | 208 (18) | 4,645 (35) | 6,309 | 305 (23) | |
— | 1,870 (14) | 1,845 | 78 (7) | 2,485 (19) | 3,136 | 118 (9) | |
— | 2,535 (19) | 2,815 | 225 (19) | — | — | — | |
1,909 (14) | 2,125 | 53 (5) | 2,079 (16) | 2,800 | 65 (5) | ||
— | 10,811 (82) | 11,852 | 1,097 (93) | 11,170 (84) | 14,680 | 1,273 (95) | |
— | 529 (4) | 718 | 27 (2) | — | — | — |
Multiple imputation was used to impute missing values of baseline CD4 count and clinical stage, and to impute outcomes in patients lost to follow-up (see
Abbreviations: NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
Age groups are indicated by the lower age, e.g., age group 15 indicating age 15–19 y, age group 20 indicating age 20–24 y, and so forth. Data from the Global Burden of Disease Study
The adjusted risk of excess mortality steeply declined with time period on ART. With reference to the first 3 mo, the eHR for the second year on treatment was 0.10, indicating a risk reduction of 90% (
Period, Characteristics, and Starting Period | eHR (95% CI) | |
— | <0.0001 | |
Month 1–3 | 1 | — |
Months 4–6 | 0.36 (0.33–0.40) | — |
Months 7–12 | 0.18 (0.15–0.22) | — |
Months 13–24 | 0.10 (0.086–0.12) | — |
— | 0.34 | |
16–29 | 1 | — |
30–39 | 1.06 (0.80–1.41) | — |
40–49 | 1.09 (0.88–1.34) | — |
≥50 | 1.27 (0.96–1.67) | — |
— | 0.044 | |
Male | 1 | — |
Female | 0.84 (0.71–0.99) | — |
— | 0.86 | |
Two NRTIs + one NNRTI | 1 | — |
Two NRTIs + one PI | 1.04 (0.30–3.68) | — |
Unknown or other combination | 0.94 (0.73–1.21) | — |
— | <0.0001 | |
<25 | 1 | — |
25–49 | 0.68 (0.58–0.81) | — |
50–99 | 0.42 (0.32–0.56) | — |
100–199 | 0.28 (0.22–0.34) | — |
≥200 | 0.19 (0.14–0.26) | — |
— | <0.0001 | |
WHO stage I/II | 0.28 (0.17–0.46) | — |
WHO stage III/IV | 1 | — |
— | 0.24 | |
Before 2005 | 1 | — |
2005 or later | 1.16 (0.91–1.49) | — |
eHRs from multivariable Poisson regression models, comparing mortality among HIV-infected patients, taking into account the background mortality among non-HIV–infected individuals in the general populations of the four countries included in the study. Models were adjusted for all variables listed in the table.
Abbreviations: NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
We examined effect modifications by adding interaction terms for variables time after starting ART, baseline CD4, and clinical stage of disease to the model. There was evidence that the effect of baseline CD4 count depended on the time period after starting ART (test of interaction,
Excess mortality declined with time on treatment and increasing baseline CD4 cell count. It was lower in women as compared to men, and higher in patients starting ART with advanced stage of disease (
CD4 Count (Cells/µl) | Clinical Stage | Time after Starting ART (mo) | ||||
1–3 | 4–6 | 7–12 | 13–24 | Overall (1–24) | ||
63.79 (44.67–91.10) | 15.87 (8.62–29.22) | 7.99 (4.87–13.09) | 4.94 (3.39–7.21) | 17.5 (14.5–21.1) | ||
18.25 (9.15–36.41) | 4.54 (1.91–10.79) | 2.29 (0.96–5.43) | 1.41 (0.75–2.67) | 4.87 (2.64–9.00) | ||
38.32 (25.15–58.38) | 14.36 (8.49–24.28) | 7.87 (3.98–15.57) | 2.70 (1.18–6.16) | 12.1 (9.09–16.0) | ||
10.96 (5.34–22.50) | 4.11 (1.81–9.35) | 2.25 (0.83–6.11) | 0.77 (0.26–2.28) | 3.36 (1.74–6.49) | ||
21.86 (11.39–41.97) | 8.80 (4.46–17.36) | 4.55 (2.22–9.33) | 3.18 (1.65–6.12) | 7.38 (4.98–10.95) | ||
6.25 (2.49–15.70) | 2.52 (0.98–6.44) | 1.30 (0.45–3.77) | 0.91 (0.36–2.29) | 2.05 (0.98–4.31) | ||
13.73 (7.20–26.19) | 7.52 (4.65–12.18) | 2.71 (1.54–4.79) | 1.81 (0.94–3.50) | 4.83 (3.56–6.56) | ||
3.93 (1.57–9.84) | 2.15 (0.95–4.87) | 0.78 (0.34–1.80) | 0.52 (0.23–1.17) | 1.35 (0.70–2.59) | ||
10.20 (7.55–13.77) | 3.50 (1.90–6.45) | 3.12 (0.19–5.01) | 0.96 (0.37–2.49) | 3.59 (2.82–4.56) | ||
2.92 (1.53–5.58) | 1.00 (0.43–2.35) | 0.89 (0.48–1.66) | 0.27 (0.08–0.94) | 1.00 (0.55–1.81) | ||
21.20 (19.21–23.38) | 7.58 (6.48–8.86) | 3.79 (2.93–4.90) | 2.15 (1.79–2.58) | 6.95 (5.95–8.13) |
Results from Poisson model that included all variables listed and allowed for interaction between baseline CD4 cell count and time after starting ART.
SMRs, overall and stratified by time period on ART, baseline CD4 cell count, and clinical stage of disease are shown in
CD4 Count (Cells/µl) | Clinical Stage | Time Period (mo) | ||||
1–3 | 4–6 | 7–12 | 13–24 | Overall (1–24) | ||
552.7 (400.1–763.5) | 142.7 (85.3–238.7) | 37.2 (22.3–62.0) | 11.5 (7.95–16.7) | 47.1 (39.1–56.6) | ||
186.3 (99.3–349.2) | 48.1 (22.7–102.0) | 12.5 (5.52–28.4) | 3.88 (2.10–7.17) | 15.8 (8.99–27.9) | ||
333.1 (233.3–475.5) | 130.4 (79.9–212.6) | 37.2 (20.1–68.9) | 7.01 (3.51–14.0) | 31.4 (26.1–37.7) | ||
112.3 (59.9–210.4) | 43.9 (20.7–93.1) | 12.5 (5.17–30.3) | 2.36 (0.95–5.85) | 10.6 (6.08–18.4) | ||
192.2 (108.5–340.5) | 80.4 (44.5–145.1) | 22.6 (11.7–43.6) | 8.04 (4.73–13.7) | 19.6 (15.1–25.5) | ||
64.8 (28.9–145.0) | 27.1 (11.9–61.7) | 7.61 (2.95–19.6) | 2.71 (1.24–5.90) | 6.59 (3.58–12.1) | ||
123.0 (70.6–214.4) | 70.6 (46.7–106.8) | 14.5 (8.67–24.1) | 5.34 (3.46–8.23) | 13.6 (11.5–16.1) | ||
41.5 (18.7–91.9) | 23.8 (11.8–48.1) | 4.87 (2.29–10.4) | 1.80 (0.98–3.31) | 4.57 (2.67–7.84) | ||
89.5 (62.1–129.0) | 34.3 (18.4–63.8) | 16.1 (11.2–23.1) | 3.39 (1.79–6.40) | 10.2 (7.63–13.7) | ||
30.2 (15.7–58.0) | 11.5 (4.98–26.8) | 5.43 (3.13–9.43) | 1.14 (0.47–2.77) | 3.44 (1.91–6.17) | ||
130.0 (110.9–152.4) | 49.6 (42.2–58.3) | 13.4 (10.4–17.3) | 4.05 (3.25–5.04) | 18.7 (17.7–19.8) |
When restricting the analysis to the three treatment programmes with rates of loss to follow-up below 10% (Khayelitsha, Gugulethu, Connaught), estimates of excess mortality and SMRs were somewhat lower, but the variation with time period, baseline CD4, and clinical stage was similar to that observed using all data (
In this collaborative study of five treatment programmes in four countries in sub-Saharan Africa, the mortality of HIV-infected patients starting ART could be compared with that estimated for the corresponding non-HIV–infected general populations. In these countries, a large proportion of deaths among young and middle-aged adults are HIV-related. We found that mortality during the first 2 y of ART was more than 18 times higher than in the general population not infected by HIV. However, there was large variability between prognostic groups and over time: in patients with very low CD4 counts and advanced clinical disease, mortality was increased over 300 times in the first 3 mo of treatment, whereas in the second year of ART, patients who started with high CD4 counts and less advanced disease had mortality rates that were comparable to those estimated for non-HIV–infected individuals.
We used excess mortality rates as well as SMRs and thus took the background mortality in the general population into account. The calculation of expected numbers of deaths was restricted to people not infected with HIV, which is crucial when the prevalence of the exposure (HIV infection) in the general population is high and SMRs are large
One limitation of our study is that the reference rates for HIV-unrelated mortality are unlikely to be completely accurate for the source populations from which the HIV-infected patients originate, and that errors in the calculation of expected number of deaths are not reflected in the confidence limits of SMRs and excess mortality rates
Our study has other limitations. Complete ascertainment of risk factors and deaths and complete follow-up of patients is difficult to achieve in treatment programmes in low-income countries
Follow-up was limited to 2 y in the present analyses, reflecting the relatively recent scale up of ART in sub-Saharan Africa, and it is possible that mortality will increase again in HIV-infected patients with longer duration of treatment. The short follow-up also meant that life expectancy of patients starting ART could not be examined. The ART Cohort Collaboration of HIV cohorts in Europe and North America recently estimated that life expectancy at age 35 y among patients on ART not infected through injecting drug use was 33 y
How do these SMRs compare with other population groups at increased risk of death due to unhealthy lifestyles, occupational exposures, or chronic conditions other than HIV infection? Few data are available for sub-Saharan Africa. White South African gold miners, compared to the white male population, had an SMR of 1.3, because of excess mortality due to lung cancer, chronic obstructive lung disease, and liver cirrhosis
Excess mortality was greater among men than among women. A recent analysis from the ART in Lower Income Countries (ART-LINC) collaboration found that although women are more vulnerable than men to becoming infected with HIV, they were equally or more likely than men to start ART
Although some HIV-infected patients starting ART in sub-Saharan Africa experienced mortality rates that were comparable with those experienced by other patients with a chronic condition, early mortality in adults starting ART continues to be high in sub-Saharan Africa
Age- and sex-specific HIV-unrelated mortality per 100 population in Côte d'Ivoire, Malawi, Zimbabwe, and South Africa, 2004. Data from the Global Burden of Disease study
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Excess mortality per 100 person-years for months 1–24 by baseline CD4 count and clinical stage of disease, and by sex and age group.
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SMRs for months 1–24 by baseline CD4 count and clinical stage of disease, and by sex and age group.
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Excess mortality per 100 person-years by time period on ART, baseline CD4 count, and clinical stage of disease in the three ART programmes with low rates of loss to follow-up (Connaught, Gugulethu, Khayelitsha).
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SMRs by time period on ART, baseline CD4 count, and clinical stage of disease in the three ART programmes with low rates of loss to follow-up (Connaught, Gugulethu, Khayelitsha).
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We are grateful to all patients, doctors, and study nurses who were involved in the participating cohort studies. The views expressed in this paper are solely the responsibility of the named authors and do not necessarily reflect the decisions or stated policy of the World Health Organization or its Member States.
antiretroviral therapy
excess hazard ratio
interquartile range
standardised mortality ratio
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